tbuckley/cabot-search huggingface dataset:
First-in-Human Study of the Reversible BTK Inhibitor Nemtabrutinib in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia and B-Cell Non–Hodgkin Lymphoma
Authors: Jennifer A. Woyach, Deborah M. Stephens, Ian W. Flinn, Seema A. Bhat, Ronald E. Savage, Feng Chai, Sudharshan Eathiraj, Sean D. Reiff, Elizabeth M. Muhowski, Lindsey Granlund, Lyndsey Szuszkiewicz, Wayne Wang, Brian Schwartz, Razi Ghori, Mohammed Z.H. Farooqui, John C. Byrd
Journal: Cancer Discovery (2023)

Nemtabrutinib is an orally bioavailable, reversible inhibitor of Bruton tyrosine kinase (BTK) and C481S mutant BTK. We evaluated the safety, pharmacology, and antitumor activity of nemtabrutinib in relapsed/refractory hematologic malignancies. Forty-eight patients with chronic lymphocytic leukemia (CLL), B-cell non-Hodgkin lymphoma (NHL), or Waldenström macroglobulinemia (WM), relapsed/refractory after ≥2 prior therapies were enrolled in the open-label, single-arm, phase I MK-1026-001 study (NCT03162536) to receive nemtabrutinib 5 to 75 mg once daily in 28-day cycles. Dose finding progressed using a 3 + 3 dose escalation design. Primary endpoints were safety and the recommended phase II dose (RP2D). Among 47 treated patients, 29 had CLL, 17 had NHL, and 1 had WM. Grade ≥3 treatment-emergent adverse events occurred in 37 (89%), most commonly neutropenia (11; 23.4%), febrile neutropenia (7; 14.9%), and pneumonia (7; 14.9%). The RP2D was 65 mg daily. An overall response rate of 75% was observed in patients with CLL at 65 mg daily. This first-in-human phase I study demonstrates the safety and preliminary efficacy of nemtabrutinib in patients with relapsed/refractory B-cell malignancies. These data support further exploration of nemtabrutinib in larger clinical studies. This article is featured in Selected Articles from This Issue, p. 5.
Antigen-loaded flagellate bacteria for enhanced adaptive immune response by intradermal injection
Authors: Feng Tao, Qingsong Ye, Yimiao Chen, Lifeng Luo, Haiheng Xu, Jialong Xu, Zhuo Feng, Chao Wang, Tao Li, Yuxuan Wen, Yiqiao Hu, Hong Dong, Xiaozhi Zhao, Jinhui Wu
Journal: Journal of Controlled Release (2023)
Parents’ Views on Autopsy, Organ Donation, and Research Donation After Neonatal Death
Authors: Elizabeth E. Crouch, Carlos Damas, William C. Bartrug, Anne Shamiyeh, Meghan Scelfo, Madeleine Dreyfus, Dawn Gano, Summer Segal, Linda S. Franck
Journal: JAMA Network Open (2023)

Parents who experience neonatal loss have the option to participate in autopsy, organ donation, and research donation. However, clinicians are uncomfortable discussing autopsy and may not be aware of research and organ donation opportunities.
Brexpiprazole for the Treatment of Agitation in Alzheimer Dementia
Authors: Daniel Lee, Mary Slomkowski, Nanco Hefting, Dalei Chen, Klaus Groes Larsen, Eva Kohegyi, Mary Hobart, Jeffrey L. Cummings, George T. Grossberg
Journal: JAMA Neurology (2023)

Agitation is a prevalent, distressing, and burdensome manifestation of Alzheimer dementia in need of an efficacious, safe, and well-tolerated treatment.
Automated Electronic Frailty Index–Identified Frailty Status and Associated Postsurgical Adverse Events
Authors: Ashish K. Khanna, Vida Motamedi, Bethany Bouldin, Timothy Harwood, Nicholas M. Pajewski, Amit K. Saha, Scott Segal
Journal: JAMA Network Open (2023)

Electronic frailty index (eFI) is an automated electronic health record (EHR)-based tool that uses a combination of clinical encounters, diagnosis codes, laboratory workups, medications, and Medicare annual wellness visit data as markers of frailty status. The association of eFI with postanesthesia adverse outcomes has not been evaluated.
Nonfunctional Adrenal Adenomas and Increased Risk of Mortality
Authors: Barbara Depczynski, Myron Lee, Andrea R. Horvath
Journal: JAMA Internal Medicine (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Neighborhood Deprivation and DNA Methylation and Expression of Cancer Genes in Breast Tumors
Authors: Brittany D. Jenkins, Emily Rossi, Catherine Pichardo, William Wooten, Margaret Pichardo, Wei Tang, Tiffany H. Dorsey, Anuoluwapo Ajao, Ruby Hutchison, Leah Moubadder, Lauren E. McCullough, Maeve Bailey-Whyte, Stefan Ambs
Journal: JAMA Network Open (2023)

Importance The biological processes that underlie the association of neighborhood environment with chronic diseases, such as cancer, remain poorly understood. Objective To determine whether differences in breast tissue DNA methylation are associated with neighborhood deprivation among Black and White women with breast cancer. Design, Setting, and Participants This cross-sectional study collected breast tissue from women undergoing surgery for breast cancer between January 1, 1993, and December 31, 2003. Participants were recruited through the University of Maryland Medical Center, with additional collection sites at Baltimore-area hospitals. Data analysis was performed from March 1 through December 1, 2022. Exposure Year 2000 census tract–level socioeconomic deprivation measured via neighborhood deprivation index (NDI) as a standardized score, with Black and White race being ascertained through self-report. Main Outcome and Measures The primary outcome was tissue DNA methylation using genome-wide measurements. The secondary outcome was tissue gene expression. Results Participants included 185 women with breast cancer (110 Black [59.5%], 75 White [40.5%]). Mean (SD) age at surgery was 56.0 (14.1) years. Neighborhood deprivation was higher for Black women than for White women (Mean [SD] NDI, 2.96 [3.03] for Black women and −0.54 [1.91] for White women; difference, −3.50; 95% CI, −4.22 to −2.79; P &amp;amp;lt; .001). In unstratified analysis, 8 hypomethylated CpG sites were identified as associated with the NDI, including sites in 2 tumor suppressor genes, LRIG1 and WWOX . Moreover, expression of the 2 genes inversely correlated with neighborhood deprivation. In the race-stratified analysis, the negative correlation between the LRIG1 gene body CpG site cg26131019 and the NDI remained significant in Black women. A neighborhood deprivation–associated decrease in gene expression was also observed for LRIG1 and WWOX in tumors from Black women. Conclusions and Relevance In this study, high neighborhood deprivation was associated with differences in tissue DNA methylation and gene expression among Black women. These findings suggest that continued investment in public health interventions and policy changes at the neighborhood level may help to remedy biological alterations that could make minoritized populations more susceptible to chronic diseases.
Disseminated juvenile xanthogranulomas with underlying neurotrophic tyrosine receptor kinase fusion and response to larotrectinib
Authors: Eun Jae Kim, Diana Bartenstein Reusch, Hannah Anthony, Birgitta Schmidt, Kristen Corey, Barbara Degar, Jennifer T Huang
Journal: British Journal of Dermatology (2023)

Recent molecular characterizations of histiocytoses, including juvenile xanthogranuloma (JXG), have identified diverse kinase gene mutations, suggesting that various targeted therapies may be promising treatments for these lesions. We herein present a case of an infant with disseminated JXG lesions with an underlying NTRK mutation who was successfully treated with larotrectinib.
Nonfunctional Adrenal Adenomas and Increased Risk of Mortality
Authors: Fabio Bioletto, Ezio Ghigo, Mirko Parasiliti-Caprino
Journal: JAMA Internal Medicine (2023)

To the Editor We read with great interest the article by Patrova et al1 on the risk of mortality in patients with nonfunctional adrenal tumors. This study addresses a topic of pivotal importance in adrenal disease that has been the subject of intense research interest in recent years.
Time to Endoscopy or Colonoscopy Among Adults Younger Than 50 Years With Iron-Deficiency Anemia and/or Hematochezia in the VHA
Authors: Joshua Demb, Lin Liu, Caitlin C. Murphy, Chyke A. Doubeni, Maria Elena Martinez, Samir Gupta
Journal: JAMA Network Open (2023)

To date, the diagnostic test completion rate and the time to diagnostic endoscopy or colonoscopy among adults with iron-deficiency anemia (IDA) and/or hematochezia have not been well characterized.
Shared Genetic Risk in the Association of Screen Time With Psychiatric Problems in Children
Authors: Yingzhe Zhang, Karmel W. Choi, Scott W. Delaney, Tian Ge, Jean-Baptiste Pingault, Henning Tiemeier
Journal: JAMA Network Open (2023)

Importance Children’s exposure to screen time has been associated with poor mental health outcomes, yet the role of genetic factors remains largely unknown. Objective To assess the extent of genetic confounding in the associations between screen time and attention problems or internalizing problems in preadolescent children. Design, Setting, and Participants This cohort study analyzed data obtained between 2016 and 2019 from the Adolescent Brain Cognitive Development Study at 21 sites in the US. The sample included children aged 9 to 11 years of genetically assigned European ancestry with self-reported screen time. Data were analyzed between November 2021 and September 2023. Exposure Child-reported daily screen time (in hours) was ascertained from questionnaires completed by the children at baseline. Main Outcomes and Measures Child psychiatric problems, specifically attention and internalizing problems, were measured with the parent-completed Achenbach Child Behavior Checklist at the 1-year follow-up. Genetic sensitivity analyses model (Gsens) was used, which incorporated polygenic risk scores (PRSs) of both exposure and outcomes as well as either single-nucleotide variant (SNV; formerly single-nucleotide polymorphism)–based heritability or twin-based heritability to estimate genetic confounding. Results The 4262 children in the sample included 2269 males (53.2%) with a mean (SD) age of 9.9 (0.6) years. Child screen time was associated with attention problems (β = 0.10 SD; 95% CI, 0.07-0.13 SD) and internalizing problems (β = 0.03 SD; 95% CI, 0.003-0.06 SD). The television time PRS was associated with child screen time (β = 0.18 SD; 95% CI, 0.14-0.23 SD), the attention-deficit/hyperactivity disorder PRS was associated with attention problems (β = 0.13 SD; 95% CI, 0.10-0.16 SD), and the depression PRS was associated with internalizing problems (β = 0.10 SD; 95% CI, 0.07-0.13 SD). These PRSs were associated with cross-traits, suggesting genetic confounding. Estimates using PRSs and SNV-based heritability showed that genetic confounding accounted for most of the association between child screen time and attention problems and for 42.7% of the association between child screen time and internalizing problems. When PRSs and twin-based heritability estimates were used, genetic confounding fully explained both associations. Conclusions and Relevance Results of this study suggest that genetic confounding may explain a substantial part of the associations between child screen time and psychiatric problems. Genetic confounding should be considered in sociobehavioral studies of modifiable factors for youth mental health.
Changes Induced by Early Hand-Arm Bimanual Intensive Therapy Including Lower Extremities in Young Children With Unilateral Cerebral Palsy
Authors: Rodrigo Araneda, Daniela Ebner-Karestinos, Julie Paradis, Anne Klöcker, Geoffroy Saussez, Josselin Demas, Rodolphe Bailly, Sandra Bouvier, Astrid Carton de Tournai, Enimie Herman, Aghiles Souki, Grégoire Le Gal, Emmanuel Nowak, Stephane V. Sizonenko, Christopher J. Newman, Mickael Dinomais, Inmaculada Riquelme, Andrea Guzzetta, Sylvain Brochard, Yannick Bleyenheuft
Journal: JAMA Pediatrics (2023)

Intensive interventions are provided to young children with unilateral cerebral palsy (UCP), classically focused on the upper extremity despite the frequent impairment of gross motor function. Hand-Arm Bimanual Intensive Therapy Including Lower Extremities (HABIT-ILE) effectively improves manual dexterity and gross motor function in school-aged children.
Further Considerations Regarding Molecular Screening and Treatment of Bacterial Vaginosis
Authors: Feng Li, Kai Liu
Journal: JAMA Pediatrics (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
The Tip of the Iceberg—Concealing of Advanced Conduction Abnormality
Authors: Pongsakorn Buraphat, Pornanong Kurusathian, Arjbordin Winijkul
Journal: JAMA Internal Medicine (2023)

This case report describes a patient in their 80s who presented with dyspnea and syncope during exercise and a history of essential hypertension and Parkinson disease.
Artificially reprogrammed stem cells deliver transcytosable nanocomplexes for improved spinal cord repair
Authors: Xin Liu, Yufei Zheng, Qingqing Wang, Lan Zhao, Zhaowei Zhang, Haoli Wang, Yang Yang, Nan Song, Jiajia Xiang, Youqing Shen, Shunwu Fan
Journal: Journal of Controlled Release (2023)
The neuropeptidergic connectome of C. elegans
Authors: Lidia Ripoll-Sánchez, Jan Watteyne, HaoSheng Sun, Robert Fernandez, Seth R. Taylor, Alexis Weinreb, Barry L. Bentley, Marc Hammarlund, David M. Miller, Oliver Hobert, Isabel Beets, Petra E. Vértes, William R. Schafer
Journal: Neuron (2023)

Efforts are ongoing to map synaptic wiring diagrams, or connectomes, to understand the neural basis of brain function. However, chemical synapses represent only one type of functionally important neuronal connection; in particular, extrasynaptic, "wireless" signaling by neuropeptides is widespread and plays essential roles in all nervous systems. By integrating single-cell anatomical and gene-expression datasets with biochemical analysis of receptor-ligand interactions, we have generated a draft connectome of neuropeptide signaling in the C. elegans nervous system. This network is characterized by high connection density, extended signaling cascades, autocrine foci, and a decentralized topology, with a large, highly interconnected core containing three constituent communities sharing similar patterns of input connectivity. Intriguingly, several key network hubs are little-studied neurons that appear specialized for peptidergic neuromodulation. We anticipate that the C. elegans neuropeptidergic connectome will serve as a prototype to understand how networks of neuromodulatory signaling are organized.
Selective IL-27 production by intestinal regulatory T cells permits gut-specific regulation of TH17 cell immunity
Authors: Chia-Hao Lin, Cheng-Jang Wu, Sunglim Cho, Rasika Patkar, William J. Huth, Ling-Li Lin, Mei-Chi Chen, Elisabeth Israelsson, Joanne Betts, Magdalena Niedzielska, Shefali A. Patel, Han G. Duong, Romana R. Gerner, Chia-Yun Hsu, Matthew Catley, Rose A. Maciewicz, Hiutung Chu, Manuela Raffatellu, John T. Chang, Li-Fan Lu
Journal: Nature Immunology (2023)
Chromosome-level genomes of three key Allium crops and their trait evolution
Authors: Fei Hao, Xue Liu, Botong Zhou, Zunzhe Tian, Lina Zhou, Hang Zong, Jiyan Qi, Juan He, Yongting Zhang, Peng Zeng, Qiong Li, Kai Wang, Keke Xia, Xing Guo, Li Li, Wenwen Shao, Bohan Zhang, Shengkang Li, Haifeng Yang, Linchong Hui, Wei Chen, Lixin Peng, Feipeng Liu, Zi-Qiang Rong, Yingmei Peng, Wenbo Zhu, John A. McCallum, Zhen Li, Xun Xu, Hui Yang, Richard C. Macknight, Wen Wang, Jing Cai
Journal: Nature Genetics (2023)
Subclinical giant cell arteritis increases the risk of relapse in polymyalgia rheumatica
Authors: Eugenio De Miguel, Rositsa Karalilova, Pierluigi Macchioni, Cristina Ponte, Edoardo Conticini, Sharon Cowley, Alessandro Tomelleri, Sara Monti, Irene Monjo, Zguro Batalov, Giulia Klinowski, Paolo Falsetti, David J Kane, Corrado Campochiaro, Alojzija Hočevar
Journal: Annals of the Rheumatic Diseases (2023)

The aim of the present study was to determine the clinical significance of subclinical giant cell arteritis (GCA) in polymyalgia rheumatica (PMR) and ascertain its optimal treatment approach.
A discrete ‘early-responder’ stromal-cell subtype orchestrates immunocyte recruitment to injured tissue
Authors: Omar K. Yaghi, Bola S. Hanna, P. Kent Langston, Daniel A. Michelson, Teshika Jayewickreme, Miguel Marin-Rodero, Christophe Benoist, Diane Mathis
Journal: Nature Immunology (2023)
Harnessing CD3 diversity to optimize CAR T cells
Authors: Rubí M.-H. Velasco Cárdenas, Simon M. Brandl, Ana Valeria Meléndez, Alexandra Emilia Schlaak, Annabelle Buschky, Timo Peters, Fabian Beier, Bryan Serrels, Sanaz Taromi, Katrin Raute, Simon Hauri, Matthias Gstaiger, Silke Lassmann, Johannes B. Huppa, Melanie Boerries, Geoffroy Andrieux, Bertram Bengsch, Wolfgang W. Schamel, Susana Minguet
Journal: Nature Immunology (2023)

Current US Food and Drug Administration-approved chimeric antigen receptor (CAR) T cells harbor the T cell receptor (TCR)-derived ζ chain as an intracellular activation domain in addition to costimulatory domains. The functionality in a CAR format of the other chains of the TCR complex, namely CD3δ, CD3ε and CD3γ, instead of ζ, remains unknown. In the present study, we have systematically engineered new CD3 CARs, each containing only one of the CD3 intracellular domains. We found that CARs containing CD3δ, CD3ε or CD3γ cytoplasmic tails outperformed the conventional ζ CAR T cells in vivo. Transcriptomic and proteomic analysis revealed differences in activation potential, metabolism and stimulation-induced T cell dysfunctionality that mechanistically explain the enhanced anti-tumor performance. Furthermore, dimerization of the CARs improved their overall functionality. Using these CARs as minimalistic and synthetic surrogate TCRs, we have identified the phosphatase SHP-1 as a new interaction partner of CD3δ that binds the CD3δ-ITAM on phosphorylation of its C-terminal tyrosine. SHP-1 attenuates and restrains activation signals and might thus prevent exhaustion and dysfunction. These new insights into T cell activation could promote the rational redesign of synthetic antigen receptors to improve cancer immunotherapy.
Abatacept and non-melanoma skin cancer in patients with rheumatoid arthritis: a comprehensive evaluation of randomised controlled trials and observational studies
Authors: Teresa A Simon, Lixian Dong, Samy Suissa, Kaleb Michaud, Sofia Pedro, Marc Hochberg, Maarten Boers, Johan Askling, Thomas Frisell, Anja Strangfeld, Yvette Meissner, Vadim Khaychuk, Alyssa Dominique, Michael A Maldonado
Journal: Annals of the Rheumatic Diseases (2023)

This study aims to evaluate non-melanoma skin cancer (NMSC) risk associated with abatacept treatment for rheumatoid arthritis (RA).
Impact of the metabolic syndrome on cardiopulmonary morbidity and mortality in individuals with lung function impairment: a prospective cohort study of the Danish general population
Authors: Jacob Louis Marott, Truls Sylvan Ingebrigtsen, Yunus Çolak, Hannu Kankaanranta, Per Sigvald Bakke, Jørgen Vestbo, Børge Grønne Nordestgaard, Peter Lange
Journal: The Lancet Regional Health - Europe (2023)

Whether the metabolic syndrome plays a role for the prognosis of individuals with lung function impairment (preserved ratio impaired spirometry (PRISm) or airflow limitation) is unclear. We hypothesised that the metabolic syndrome in individuals with lung function impairment is associated with increased cardiopulmonary morbidity and mortality.The Copenhagen General Population Study was initiated in 2003 based on a random sample of white men and women aged 20-100 years drawn from the Danish general population. The risk of ischemic heart disease/heart failure, respiratory disease, and all-cause mortality was analysed with Cox models adjusted for age, sex, current smoking, and asthma during 15 years of follow-up.Among 106,845 adults, 86,159 had normal lung function, 6126 had PRISm, and 14,560 had airflow limitation. We observed 10,448 hospital admissions for ischemic heart disease/heart failure, 21,140 for respiratory disease, and 11,125 deaths. Individuals with versus individuals without the metabolic syndrome generally had higher 5-year absolute risk of all outcomes, including within those with normal lung function, mild-moderate-severe PRISm, and very mild-mild-moderate-severe airflow limitation alike. Compared to individuals without the metabolic syndrome and with normal lung function, those with both the metabolic syndrome and severe PRISm had hazard ratios of 3.74 (95% CI: 2.53-5.55; p < 0.0001) for ischemic heart disease/heart failure, 5.02 (3.85-6.55; p < 0.0001) for respiratory disease, and 5.32 (3.76-7.54; p < 0.0001) for all-cause mortality. Corresponding hazard ratios in those with both the metabolic syndrome and severe airflow limitation were 2.89 (2.34-3.58; p < 0.0001) for ischemic heart disease/heart failure, 5.98 (5.28-6.78; p < 0.0001) for respiratory disease, and 4.16 (3.50-4.95; p < 0.0001) for all-cause mortality, respectively. The metabolic syndrome explained 13% and 27% of the influence of PRISm or airflow limitation on ischemic heart disease/heart failure and all-cause mortality.The metabolic syndrome conferred increased risk of cardiopulmonary morbidity and mortality at all levels of lung function impairment.Danish Lung Foundation, Danish Heart Foundation, Capital Region of Copenhagen, and Boehringer Ingelheim. JV is supported by the NIHR Manchester BRC.
Impact of the COVID-19 pandemic on implementation of novel guideline-directed medical therapies for heart failure in Germany: a nationwide retrospective analysis
Authors: Fabian Kerwagen, Uwe Riemer, Rolf Wachter, Stephan von Haehling, Amr Abdin, Michael Böhm, Martin Schulz, Stefan Störk
Journal: The Lancet Regional Health - Europe (2023)

Guideline-directed medical therapy (GDMT) is the cornerstone in the treatment of patients with heart failure and reduced ejection fraction (HFrEF) and novel substances such as sacubitril/valsartan (S/V) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) have demonstrated marked clinical benefits. We investigated their implementation into real-world HF care in Germany before, during, and after the COVID-19 pandemic period.